WO2022031057A1 - 활성화 부위가 일시적으로 비활성화된 톨-유사 수용체 7 또는 8 작용자와 기능성 약물의 결합체 및 그 용도 - Google Patents

활성화 부위가 일시적으로 비활성화된 톨-유사 수용체 7 또는 8 작용자와 기능성 약물의 결합체 및 그 용도 Download PDF

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WO2022031057A1
WO2022031057A1 PCT/KR2021/010298 KR2021010298W WO2022031057A1 WO 2022031057 A1 WO2022031057 A1 WO 2022031057A1 KR 2021010298 W KR2021010298 W KR 2021010298W WO 2022031057 A1 WO2022031057 A1 WO 2022031057A1
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agonist
conjugate
receptor
toll
antibody
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PCT/KR2021/010298
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English (en)
French (fr)
Korean (ko)
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임용택
이상남
진승모
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성균관대학교산학협력단
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Priority claimed from KR1020210102226A external-priority patent/KR20220017378A/ko
Application filed by 성균관대학교산학협력단 filed Critical 성균관대학교산학협력단
Priority to JP2023507715A priority Critical patent/JP2023536954A/ja
Priority to CN202180056797.5A priority patent/CN116056725A/zh
Priority to US18/040,323 priority patent/US20230277525A1/en
Priority to EP21852799.2A priority patent/EP4194010A1/de
Publication of WO2022031057A1 publication Critical patent/WO2022031057A1/ko

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Definitions

  • the present invention relates to a conjugate in which a functional drug is bound to the activation site of a Toll-like receptor 7 or 8 agonist, and more particularly, the functional drug is bound to the active site of the Toll-like receptor 7 or 8 agonist.
  • Toll-like receptor 7 or 8 agonist function is temporarily inhibited, and the function is kinetically recovered at a predetermined time interval, the present invention relates to a conjugate, its use, and the like.
  • an immune response is a series of reactions caused by activated immune cells to foreign and endogenous substances, that is, antigens. Immune cells recognize this and are activated, secreting factors such as cytokines to induce an inflammatory response.
  • Toll-like receptor 7 or 8 agonist-based substances are used as adjuvants to induce cellular immune responses, and imidazoquinoloine-based agonists, 8-hydroxyadenine-based agonist, pteridone-based agonist, 2-aminopyrimidine-based agonist, benzoazepine -based agonist), thiaoxoguanosine-based agonist (7-thia-8-oxoguanosine-based agonist), etc. are known (US Patent Publication 2012-0294885).
  • Toll-like receptors 7 or 8 agonists are known to effectively induce humoral immunity as well as cellular immunity as agonists of Toll-like receptors 7 or 8 in endosomes.
  • MDSC, Treg, M2 which are immunosuppressive cells that help cancer growth and metastasis, by performing immunosuppressive action at the injection site or tumor microenvironment, beyond the function of an adjuvant, toll-like receptor 7 or 8 agonists
  • functions such as macrophage
  • these multifunctional Toll-like receptor 7 or 8 agonists have difficulty in dispersing in aqueous solution due to their molecular structure.
  • the toll-like receptor 7 or 8 agonist prepared by this method still has the possibility of causing toxicity by inducing a non-specific immune response in the body because its active site is still exposed to the outside. Have.
  • the immune activation function of the Toll-like receptor 7 or 8 agonist is inhibited by the chemical binding of the activation site, and the immune activation function is recovered in the injection site, the tumor microenvironment or the target immune cell. ), if it can be manufactured to exhibit kinetic properties that can control the immune activation efficacy according to time points, non-specific toxicity and induction of immune responses by Toll-like receptor 7 or 8 agonists can be minimized.
  • the present invention has been devised to solve the problems in the prior art as described above, and the immune activation function of the toll-like receptor 7 or 8 agonist is temporarily inhibited, and then the injection site, the tumor microenvironment or the target cell
  • the present invention provides a conjugate of a Toll-like receptor 7 or 8 agonist and a functional drug, wherein the conjugate is capable of cleaving a functional drug and an active site of a Toll-like receptor 7 or 8 agonist It provides a conjugate, characterized in that it is bound by a linker (cleavable linker). More specifically, the conjugate chemically binds one end of the cleavable linker to the active site of the Toll-like receptor 7 or 8 agonist, that is, the site exhibiting the biological activity of the Toll-like receptor 7 or 8 agonist. Thus, the toll-like receptor 7 or 8 agonist is temporarily inactivated, and a functional drug is chemically bound to the other end of the linker.
  • a linker cleavable linker
  • the functional drug primarily acts on the conjugate, and the inactivated form of Toll-like receptor 7 or 8 agonist is kinetic by cleavage of the linker at the injection site, in the tumor microenvironment or in the target cell. (kinetically) characterized in that the activation site (active site) is restored to act secondary.
  • the cleavable linker is chemical in the binding site by any one or more factors selected from the group consisting of enzyme, pH, redox potential, temperature, ultrasound, magnetic, and light source. It is characterized in that the bond is cleaved.
  • the cleavable linker is preferably a benzyl elimination-based linker, a trialkyl lock-based linker, a bicine-based linker based linker), an acid-degradable linker (acid labile linker), a lysosomally cleavable peptide, and a cathepsin B cleavable peptide (capthepsin B cleavable peptide) Any one or more selected from the group consisting of, more preferably For example, carbamate, disulfide, hydrazine, ester, peptide, azide, beta-glucuronidine ( ⁇ -Glucuronide) and combinations thereof It is characterized in that it is a linker containing one or more bonds selected from the group consisting of.
  • the two can be linked by chemically binding to a Toll-like receptor 7 or 8 agonist and a functional drug, respectively, and exogenous factors (enzymes, Redox potential, GSH, pH, etc.) and/or exogenous factors in the body. If the bond can be cut by (redox, pH, temperature, photo/light, magnetic, ultrasound, electrical responsive, etc.), the present invention is not limited thereto.
  • the cleavable linker further comprises an alkyl derivative such as ethylene oxide or ethylene glycol at both ends or one end, so that in the aqueous solution of the conjugate It is characterized by increasing the solubility and flexibility of
  • the toll-like receptor 7 or 8 agonist is preferably an imidazoquinoloine-based agonist or an 8-hydroxyadenine-based agonist.
  • pteridone-based agonist aminopyrimidine-based agonist, benzoazepine-based agonist, and thiaoxoguanosine-based action
  • Toll-like receptor 7 or 8 agonist characterized in that it is at least one selected from the group consisting of 7-thia-8-oxoguanosine-based agonist, but can exhibit an inactive form by binding a cleavable linker to the activation site If it is, it is not limited to this.
  • the functional drug is preferably an antibody, antibody fragment, single chain antibody, anticancer agent, antigen, cytokine, protein, peptide, amino acid, oligonucleotide, enzyme, lipid, small molecule compound, sugar It may be any one or more selected from the group consisting of proteins and targeting ligands, and more preferably any one or more selected from the group consisting of antibodies, protein-based drugs, sensitizers, and anticancer agents.
  • -A drug capable of binding to a receptor-like 7 or 8 agonist is not limited thereto.
  • the present invention provides a composition for controlling immune function comprising the conjugate as an active ingredient.
  • the composition for controlling immune function is characterized in that it activates any one or more immune cells selected from the group consisting of antigen-presenting cells, B cells, natural killer cells (NK cells) and T cells.
  • immune cells selected from the group consisting of antigen-presenting cells, B cells, natural killer cells (NK cells) and T cells.
  • the composition for controlling immune function is characterized in that it modulates the function of any one or more immune cells selected from the group consisting of Treg (regulatory T cell), MDSC (myeoloid derived suppressor cells), and M2 macrophage. do it with Treg (regulatory T cell), MDSC (myeoloid derived suppressor cells), and M2 macrophage. do it with Treg (regulatory T cell), MDSC (myeoloid derived suppressor cells), and M2 macrophage.
  • the composition for controlling immune function can induce the activation of immune cells or control the function of immunosuppressive cells at the injection site or the tumor microenvironment, preferably an antigen Inducing immune activation or immunosuppression of presenting cells (dendritic cells, macrophage, etc.), natural killer cells (NK cells), T cells , M2 macrophage, etc.) can control the immune function of the body.
  • immunosuppressive cells preferably an antigen Inducing immune activation or immunosuppression of presenting cells (dendritic cells, macrophage, etc.), natural killer cells (NK cells), T cells , M2 macrophage, etc.
  • the composition for controlling immune function is anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-KIR, anti-LAG3, anti- CD137, anti-OX40, anti-CD276, anti-CD27, anti-GITR, anti-TIM3, anti-41BB, anti-CD226, anti-CD40, anti-CD70, anti-ICOS, anti-CD40L, anti-BTLA, It may further include any one or more antibodies selected from the group consisting of anti-TCR, and anti-TIGIT.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the conjugate as an active ingredient.
  • the pharmaceutical composition may further include substances generally used for the treatment of cancer, such as chemical anticancer agents, immune checkpoint inhibitors, and the like. Since the pharmaceutical composition can effectively activate immune functions in the body by including the conjugate of the present invention, it is possible to enhance the efficacy of existing chemical anticancer agents, immune checkpoint inhibitors, and the like.
  • the pharmaceutical composition is characterized in that it inhibits cancer proliferation, metastasis, recurrence, or resistance to anticancer therapy.
  • the cancer is preferably breast cancer, colorectal cancer, rectal cancer, lung cancer, colon cancer, thyroid cancer, oral cancer, pharyngeal cancer, laryngeal cancer, cervical cancer, brain cancer, ovarian cancer, bladder cancer, kidney cancer, liver cancer , pancreatic cancer, prostate cancer, skin cancer, tongue cancer, uterine cancer, stomach cancer, bone cancer, blood cancer, etc., but is not limited thereto.
  • the present invention provides a method for preventing or treating cancer comprising administering to an individual a composition comprising the conjugate as an active ingredient.
  • the present invention provides a use for preventing or treating cancer of a composition comprising the conjugate as an active ingredient.
  • the present invention provides the use of the conjugate for producing a medicament used for the prevention or treatment of cancer.
  • the present invention also provides a functional drug and a toll-, comprising the steps of a) chemically binding a cleavable linker to the activation site of a toll-like receptor 7 or 8 agonist, and b) binding the functional drug to the linker.
  • Methods for preparing conjugates of receptor-like 7 or 8 agonists are provided.
  • the conjugate of the functional drug according to the present invention and a toll-like receptor 7 or 8 agonist whose activity is temporarily inhibited is a functional drug that primarily acts and a toll-like receptor 7 or 8 agonist capable of inducing a synergistic effect therewith. It is possible to maximize the synergistic effect while minimizing the non-specific immune response and toxicity by acting secondarily over a period of time.
  • the functional drug and the Toll-like receptor 7 or 8 agonist are gradually separated, and the activation site of the Toll-like receptor 7 or 8 agonist is kinetic
  • the toxicity of Toll-like receptor 7 or 8 agonists can be minimized, and at the same time, because it continuously reacts with Toll-like receptors for a long time, immune cells are better than those when Toll-like receptor agonists are used alone.
  • By increasing the persistence of immune activation it is possible to significantly increase the therapeutic effect.
  • the antibody is applied as a functional drug, the Toll-like receptor 7 or 8 agonist chemically bound to the functional drug according to the present invention (a functional drug-toll-like receptor 7 or 8 agonist conjugate), the target specificity of the antibody
  • apoptosis of cancer cells that are specifically targeted by the antibody and the cancer antigen produced therefrom binds with the adjuvant function of a Toll-like receptor 7 or 8 agonist, thereby inducing a so-called in-situ vaccination effect.
  • the functional drug-Toll-like receptor 7 or 8 agonist conjugate can induce immune activation of antigen-presenting cells (dendritic cells, macrophage, etc.), natural killer cells (NK cells), T cells, etc., and the injection site Alternatively, since it can regulate the functions of immune cells (regulatory T cell (Treg), myeoloid derived suppressor cells (MDSC), M2 macrophage, etc.) that have an immunosuppressive action in the tumor microenvironment, it can exhibit anticancer effect alone as well as Rather, if the conjugate is prepared using an immune checkpoint inhibitor, a chemical anticancer agent, etc. as a functional drug, the anticancer effect may be significantly increased by a synergistic effect.
  • antigen-presenting cells dendritic cells, macrophage, etc.
  • NK cells natural killer cells
  • T cells etc.
  • the injection site since it can regulate the functions of immune cells (regulatory T cell (Treg), myeoloid derived suppressor cells (MDSC), M2 macro
  • the conjugate of the present invention can be effectively applied to all functional drugs that can be administered in combination with a Toll-like receptor 7 or 8 agonist, thereby reducing side effects and improving the therapeutic effect, so that it can be widely used in various fields. It is expected.
  • FIG. 1 is a diagram showing a representative linker for binding a Toll-like receptor 7 or 8 agonist and a functional drug according to an embodiment of the present invention.
  • FIG. 2 is a representative anticancer agent containing an amine group according to an embodiment of the present invention, an example of a conjugate of an anticancer agent containing an amine group having a bond cleaved by a reducing agent and a Toll-like receptor 7 or 8 agonist, and a reducing agent It is a diagram briefly showing the mechanism of cutting by
  • FIG. 3 is a diagram schematically illustrating an example of a conjugate of an anticancer agent containing an amine group having a bond cleaved under acidic conditions and a Toll-like receptor 7 or 8 agonist, and a cleavage mechanism according to an embodiment of the present invention.
  • FIG. 4 is a representative anticancer agent containing a hydroxyl group according to an embodiment of the present invention, beta-An example of a conjugate of an anticancer agent having a bond cleaved by glucuronidase and a Toll-like receptor 7 or 8 agonist; And it is a diagram briefly showing the cutting mechanism.
  • FIG. 5 is a diagram schematically illustrating an example of a conjugate of an anticancer agent including a hydroxyl group having a bond cleaved by a protease and a toll-like receptor 7 or 8 agonist according to an embodiment of the present invention, and a cleavage mechanism.
  • FIG. 6 is a diagram schematically illustrating a representative linker and a linkage mechanism for synthesizing a conjugate between a protein-based drug and a Toll-like receptor 7 or 8 agonist according to an embodiment of the present invention.
  • FIG. 7 is a diagram schematically illustrating an example of a conjugate of a protein-based drug having a bond cleaved by a reducing agent and a Toll-like receptor 7 or 8 agonist according to an embodiment of the present invention, and a cleavage mechanism.
  • FIG. 8 is an example of a conjugate of a protein-based drug having a bond that is cleaved by the concentration of hydrogen ions inside a cell according to an embodiment of the present invention and a Toll-like receptor 7 or 8 agonist, and briefly the cleavage mechanism; the drawing shown.
  • FIG. 9 is a beta-according to an embodiment of the present invention, an example of a conjugate of a protein-based drug having a bond cleaved by glucuronidase and a Toll-like receptor 7 or 8 agonist, and a simplified mechanism of cleavage It is a drawing that is clearly shown.
  • FIG. 10 is a diagram schematically illustrating an example of a conjugate of a protein-based drug having a bond cleaved by a reducing agent and a Toll-like receptor 7 or 8 agonist, and a cleavage mechanism according to an embodiment of the present invention.
  • FIG. 11 is an example of a conjugate of a protein-based drug and a Toll-like receptor 7 or 8 agonist having a bond that is cleaved by the concentration of hydrogen ions inside the cell according to an embodiment of the present invention, and briefly the cleavage mechanism the drawing shown.
  • FIG. 12 is a beta-according to an embodiment of the present invention, a protein-based drug having a bond cleaved by glucuronidase and a toll-like receptor 7 or 8 agonist, an example of a conjugate, and a simplified mechanism of cleavage It is a drawing that is clearly shown.
  • FIG. 13 is a representative type of sensitizer according to an embodiment of the present invention, an example of a conjugate of a sensitizer having a bond cleaved by a reducing agent and a Toll-like receptor 7 or 8 agonist, and a cleavage mechanism briefly the drawing shown.
  • FIG. 14 is an example of a conjugate of a sensitizer containing a carboxyl group having a bond cleaved under acidic conditions and a Toll-like receptor 7 or 8 agonist according to an embodiment of the present invention, and a diagram schematically showing the cleavage mechanism to be.
  • 16 is a view showing the results of confirming the anticancer effect of the AAC-001 conjugate according to an embodiment of the present invention by the size of the cancer.
  • 17 is a view showing the results of confirming the anticancer effect of the AAC-001 conjugate according to an embodiment of the present invention as a survival rate.
  • FIG. 18 is a view showing the results of confirming the effect of the AAC-001 conjugate on the secretion of inflammatory cytokines in the blood according to an embodiment of the present invention.
  • FIG. 19 is a view briefly showing the mechanism of the AAC-002 conjugate according to an embodiment of the present invention. More specifically, it is a schematic diagram showing the mechanism of action in a cell of a conjugate of an antibody and a Toll-like receptor 7 or 8 agonist, wherein the antibody and the Toll-like receptor 7 or 8 agonist are separated by the intracellular environment to separate the toll-like receptor 7 or 8 agonist in an inactive state -Represents the process by which a receptor-like 7 or 8 agonist changes to an activated state.
  • 20 is a view showing the results of confirming the effect of the AAC-002 conjugate on the secretion of inflammatory cytokines in the blood according to an embodiment of the present invention.
  • 21 is a view showing the results of confirming that the conjugate of a protein antigen having a bond cleaved by cathepsin-ratio and resiquimod forms nanoparticles of about 99.7 nm in aqueous solution.
  • FIG. 22 is a schematic diagram showing the structure and function of a conjugate of a functional drug and a Toll-like receptor 7 or 8 agonist, wherein the functional drug is bound to the activation site of the Toll-like receptor 7 or 8 agonist with a cleavable linker, It shows the difference between inactivated kinetically activating conjugates and conventional conjugates in which a functional substance is bound to a site other than the activating site. Kinetically activating conjugates are initially effective only in the efficacy of functional substances, and after the cleavable linker reacts, the efficacy of the toll-like receptor 7 or 8 agonist, which was in an inactive state, is secondarily kinetically regenerated in response to stimulation. This dynamic action cannot be realized with Conventional conjugates that maintain the function of functional substances from the beginning and the dual active state of toll-like receptor agonists.
  • the present inventors suppressed the non-specific initial immune response of Toll-like receptor 7 or 8 agonists, thereby reducing side effects and at the same time combining various functional drugs, which can be administered in combination with a single administration, and Toll-like receptor 7 or 8 action
  • the functional drug primarily works by binding the functional drug to the activation site of the Toll-like receptor 7 or 8 agonist using a cleavable linker, and then temporarily activates the immune system
  • This inhibited Toll-like receptor agonist specifically recovers the immune activation function at the injection site, in the tumor microenvironment, or in the target cell, and thus a conjugate that works secondarily was invented (FIG. 22).
  • the inhibition may mean that the function of the activation site of the toll-like receptor 7 or 8 agonist is retarded.
  • the functional drug of the present invention and a conjugate of a Toll-like receptor 7 or 8 agonist kinetically or kinetically coordinates the activity of a functional drug and a Toll-like receptor 7 or 8 agonist, compared to conventional conjugates. The difference is that it can be dynamically modulated.
  • toll-like receptor agonist refers to a ligand that directly or indirectly acts on a toll-like receptor, a membrane protein involved in innate immunity, and the production of endogenous or exogenous ligands. It may mean a component capable of causing a signal transduction response through a signaling pathway.
  • the Toll-like receptor agonist may be a natural Toll-like receptor agonist or a synthetic Toll-like receptor agonist, and a Toll-like receptor 1 agonist, Toll-like receptor 2 agonist, Toll-like receptor 3 an agonist, a Toll-like receptor 4 agonist, a Toll-like receptor 5 agonist, a Toll-like receptor 7 or 8 agonist, a Toll-like receptor 9 agonist, and the like.
  • the toll-like receptor 7 or 8 agonist refers to a ligand capable of inducing a signal transduction response through TLR-7 or 8, for example, an imidazoquinoloine-based agonist, a hydroxyadenine type.
  • the imidazoquinoline-based compound is WO 2018 196823, WO 2011 049677, WO 2011 027022, WO 2017 102652, a compound or a pharmaceutically acceptable salt of the type mentioned in WO 2019 040491 and the like.
  • the hydroxyadenine-based compound is WO 2012 080730, WO 2013 068438, WO 2019 036023, WO 2019 035969, WO 2019 035970, WO 2019 035971, WO 2019 035968, CN 108948016, US 2014 8846697, WO 2016 023511, WO 2017 133683, WO 2017 133686, WO 2017 133684, WO 2017 133687, WO 2017 076346, WO 2018 210298, WO 2018 095426, WO 2018 068593, WO 2018 078149, WO 2018 041763, etc. including, but not limited to.
  • the compound of the pteridone series includes compounds or pharmaceutically acceptable salts of the types mentioned in US 2010 0143301, WO 2016 007765, WO 2016 044182, WO 2017 035230, WO 2017 219931, WO 2011 057148, CN 1087 94486, etc. , but is not limited thereto.
  • the aminopyrimidine-based compounds are WO 2010 133885, WO 2012066335, WO 2012 066336, WO 2012 067268, WO 2013 172479, WO 2012 136834, WO 2014 053516, WO 2014 053595, US 2018 0215720, WO 2012 156498, WO 2014 076221, WO 2016 141092, WO 2018 045144, WO 2015 014815, WO 2018 233648, WO 2014 207082, WO 2014 056593, WO 2018 002319, WO 2013 117615, etc.
  • the benzoazepine-based compounds are WO 2007 024612, WO 2010 014913, WO 2010 054215, WO 2011 022508, WO 2011 022509, WO 2012 097177, WO 2012 097173, WO 2016 096778, WO 2016 142250, WO 2017 202704, WO 2017 202703 , WO 2017 216054, WO 2017 046112, WO 2017 197624, etc. or a pharmaceutically acceptable salt.
  • the thioxoguanosine-based compound includes, but is not limited to, compounds or pharmaceutically acceptable salts of the types mentioned in WO 2016 180691, WO 2016 055553, WO 2016 180743, WO 2016 091698, and the like.
  • toll-like receptor 7 or 8 compounds or pharmaceutically acceptable salts mentioned in PCT/US2009/035563, PCT/US2015/028264, PCT/US2016/020499, WO 2015 023598, PCT/US 2015/039776, etc. may be included. have.
  • Imiquimod, Resiquimod, Dactolisib, Gardiquimod, Sumanirole, Motolimod, Vesatolimod , Loxoribine, SM360320, CL264, 3M-003, IMDQ, Compound 54, etc. but is not limited thereto, and toll-like receptors 7 or 8 that can be easily guessed by those in the art All cases of the operator are included.
  • the toll-like receptor 7 or 8 agonist is a toll-like receptor agonist, saponin, antiviral peptide, inflammasome inducer, NOD ligand, CDS ligand (cytosolic DNA sensor ligand), STING (stimulator of interferon genes) ligand, emulsion (emulsion), alum (alum) and can be replaced with one or more immunoactivating substances selected from the group consisting of combinations thereof, and delivered into the cell Toll-like receptor 3 agonist or Toll-like receptor 9 agonist having a receptor inside the endosome may also be applied in the same concept to synthesize an antibody and a conjugate, but is not limited thereto.
  • cleavable linker includes a cleavable bond, and conditions such as low pH in the body, enzymes, glutathione, such as the physiological environment of the tumor microenvironment, endosomes in cells and lysosomes ; Or an external stimulus, that is, a linker that can be cleaved by a specific stimulus such as temperature, redox potential, ultrasound, magnetic field, near-infrared light, etc., preferably carbamate, disulfide ), hydrazine, ester, peptide, azide, beta- refers to a linker containing a bond such as glucuronidine ( ⁇ -Glucuronide), but if it is in a cleavable form It is not limited thereto.
  • the conjugate is an injection site, various enzymes present in the tumor microenvironment or cells, Acid phosphatase, Acid phyrophosphatase, Phosphodiesterase, Phosphoprotein phosphatase, Phosphatidic acid phosphatase, Arylsulfatase, Proteases, Cathepsins, Collagenase, Arylamidase, Arylamidase ribonuclease, Acid deoxyribonuclease, Lipases, Triglyceride lipase, Phospholipase, Esterase, Carboxyesterase, Clucocerebrosidase, Galactocerebrosidase, Sphingomyelinase, Glycosidases, alpha-Glucosidase, beta-Glucosidase, alpha-, alpha-Galactosidase, Man, -, beta-Galactosidase
  • the term “functional drug” refers to all drugs having a biological function having a function that can be used for diagnosis, prevention, treatment, etc. of a disease, and preferably an antibody, antibody fragment, single Chain antibodies, anticancer agents, antigens, cytokines, proteins, peptides, amino acids, oligonucleotides, enzymes, lipids, low molecular weight compounds, glycoproteins, targeting ligands, etc., more preferably anticancer agents, antibodies, protein-based drugs, sensitizers, etc. However, it is not limited thereto.
  • Examples of the functional drug include a DNA topoisomerase inhibitor, a microtubule inhibiting drug, a DNA damaging agent, an antimetabolite, a nucleoside analog. , antisense oligonucleotides, locked nucleic acid (LNA), short interfering RNA (siRNA), microRNA (miRNA), aptamer, peptide nucleic acid (PNA), phosphorodiamidate morpholino oligonucleotides (PMO), antisense Bcl-2 oligonucleotides, antisense HIF-1 ⁇ oligonucleotides, antisense Survivin oligonucleotides, cell adhesion peptides, Cell penetrating peptide, receptor ligand, targeting carbohydrate molecule, lectin, RGD peptide, selectin, TAT, Penetratin, (Arg) 9, folic acid, and the like.
  • LNA locked nucleic acid
  • siRNA short interfering
  • microtubulin structure synthesis inhibitors used in the treatment of cancer It may be a DNA alkylator, a ribosome inhibitor, a protein toxin, a radioactive isotope, or the like.
  • maytansinoids maytansinoid
  • auristatin auristatin
  • dolastatin dolastatin
  • tube lysin tubulysin
  • calicheamicin calicheamicin
  • pyrrolobenzodiazepines pyrrolobenzodiazepines
  • doxorubicin doxorubicin
  • Duocamycin carboplatin (paraplatin) [carboplatin (paraplatin)], cisplatin, cyclophosphamide, ifosfamide, nidran, nitrogen mustard (mechlorethamine hydrochloride) [nitrogen mustar (mechlorethamine HCL)], bleomycin, mitomycin C, cytarabine, flurouracil, gemcitabine, trime Trimetrexate, methotrexate, etoposide, vinblastine, vinorelbine, alimta, altretamine, procarbazine, taxol (tax
  • the form of a stereoisomer or derivative thereof may also be included.
  • the auristatin may be monomethyl auristatin E (monomethyl auristatin E) or monomethyl auristatin F (monomethyl auristatin F), but is not limited as long as it is a substance used for the treatment of cancer.
  • the sensitizer may be protoporphrin, hematoporphrin monomethryl ether, pheophorbide A, photofrin, or the like, but is not limited thereto as long as it is a chemical sensitizer or optical sensitizer capable of remarkably promoting a chemical reaction or physical phenomenon.
  • antibody refers to a protein molecule serving as a receptor for an antigen that specifically recognizes an antigen, including an immunoglobulin molecule having immunological reactivity with a specific antigen, and a polyclonal antibody , monoclonal antibodies, full-length antibodies, and antibody fragments comprising an antigen-binding domain.
  • a full-length antibody has a structure having two full-length light chains and two full-length heavy chains, and each light chain is connected to the heavy chain by a disulfide bond.
  • the whole antibody includes IgA, IgD, IgE, IgM and IgG, and IgG is a subtype, including IgG1, IgG2, IgG3 and IgG4.
  • the antibody fragment refers to a fragment having an antigen-binding function, and includes Fab, Fab' F(ab')2, scFv, and Fv.
  • the Fab has a structure having a light chain and heavy chain variable regions, a light chain constant region and a heavy chain first constant region (CH1), and has one antigen-binding site.
  • Fab' differs from Fab in that it has a hinge region comprising one or more cysteine residues at the C-terminus of the heavy chain CH1 domain.
  • the F(ab')2 antibody is produced by forming a disulfide bond with a cysteine residue in the hinge region of Fab'.
  • Fv refers to a minimal antibody fragment having only a heavy chain variable region and a light chain variable region.
  • dsFv double chain Fv
  • scFv single chain Fv
  • the heavy chain variable region and the light chain variable region are covalently linked through a peptide linker.
  • Such antibody fragments can be obtained using proteolytic enzymes (for example, Fab can be obtained by restriction digestion of the whole antibody with papain, and F(ab')2 fragments can be obtained by digestion with pepsin), preferably It can be produced through genetic recombination technology.
  • the antibody of the present invention may be a native antibody or a recombinant antibody.
  • a native antibody refers to an antibody that has not been genetically engineered, and the risk of immunogenicity that a genetically engineered antibody may have in vivo may be significantly lower.
  • Recombinant antibody refers to a genetically engineered antibody, and has the ability to add antigen binding force or desired characteristics through genetic manipulation. Examples of the antibody may be an antibody that specifically binds to DEC205, CD206, DC-SIGN, DNGR1, CD11c, Fc ⁇ R, PD-L1, PD-1, CD47, SIRPalpha, Ly6G, IL-6, Gr-1, etc.
  • Immune checkpoint inhibitors anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-KIR, anti-LAG3, anti-CD137, anti-OX40, anti-CD276, anti-CD27 , anti-GITR, anti-TIM3, anti-41BB, anti-CD226, anti-CD40, anti-CD70, anti-ICOS, anti-CD40L, anti-BTLA, anti-TCR, anti-TIGIT, and the like.
  • a drug for controlling immune function is a composition comprising a conjugate of a functional drug of the present invention and a Toll-like receptor 7 or 8 agonist as an active ingredient, and can activate immune cells and regulate the function of immunosuppressive cells, , refers to drugs that make the body's immune function work normally.
  • prevention refers to any action that suppresses or delays the onset of diseases such as cancer by administration of the composition according to the present invention.
  • treatment refers to any action in which symptoms such as cancer are improved or beneficially changed by administration of the composition according to the present invention.
  • the term "individual or subject” refers to a subject to which the composition of the present invention can be administered, and the subject is not limited.
  • cancer refers to various hematologic cancers, malignant solid tumors, and the like, which can expand locally by infiltration and systematically through metastasis.
  • specific examples of cancer include colorectal cancer, adrenal cancer, bone cancer, brain cancer, breast cancer, bronchial cancer, colon and/or rectal cancer, gallbladder cancer, gastrointestinal cancer, head and neck cancer, kidney cancer, laryngeal cancer, liver cancer , lung cancer, neural tissue cancer, pancreatic cancer, prostate cancer, parathyroid cancer, skin cancer, stomach cancer, thyroid cancer, and the like.
  • cancers include adenocarcinoma, adenoma, basal cell carcinoma, cervical dysplasia and carcinoma in situ, Ewing sarcoma, squamous cell carcinoma, axillary cell carcinoma, malignant brain tumor, blast cell carcinoma, intestinal ganglion neuroma, hyperplastic corneal nerve carcinoma, islet cell carcinoma, Kaposi cancer, leiomyoma, leukemia, lymphoma, malignant carcinoma, malignant melanoma, malignant hypercalcemia, Marpanoidhabitus cancer, sheep cancer, metastatic skin cancer, mucosal neuroma, myelodysplastic syndrome, myeloma, filamentous sarcoma, neuroblastoma, osteosarcoma, bone Primary and other sarcoma, ovarian cancer, pheochromocytoma, polycythemia vera, primary brain tumor, small cell lung cancer, ulcerative and papillary squamous cell carcinoma, seminothelioma, soft tissue sarcom
  • the term "pharmaceutical composition” may be characterized in the form of capsules, tablets, granules, injections, ointments, powders, or beverages, and the pharmaceutical composition is intended for humans.
  • the pharmaceutical composition is not limited thereto, but may be formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions, respectively, according to conventional methods.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, dyes, fragrances, etc. for oral administration, and in the case of injections, buffers, preservatives, pain-free agents
  • a topical agent, solubilizer, isotonic agent, stabilizer, etc. can be mixed and used, and in the case of topical administration, a base, excipient, lubricant, preservative, etc. can be used.
  • the dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
  • oral administration in the case of oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in the form of unit dose ampoules or multiple doses. have.
  • it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
  • suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used.
  • it may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, and the like.
  • the route of administration of the pharmaceutical composition according to the present invention is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical , sublingual or rectal. Oral or parenteral administration is preferred.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrabursar, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.
  • the pharmaceutical composition of the present invention depends on several factors including the activity of the specific compound used, age, weight, general health, sex, formula, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated.
  • the dosage of the pharmaceutical composition may vary depending on the patient's condition, body weight, degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art, and 0.0001 to 500 mg per day It can be administered at /kg or 0.001 to 500 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.
  • the pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
  • the separated organic solution layer was washed with brine, and then moisture was removed using anhydrous sodium sulfate (50 g).
  • the organic solution layer from which moisture was removed was filtered using a filter and concentrated under low pressure, and the concentrated reaction product was stirred for 30 minutes using a mixed solution of methyl tert-butyl ether and methanol (15/1, v/v). did After separation using a filter, the mixture was dried under low pressure to obtain compound 6 (18 g, 60%, yellow solid). The structure of the obtained compound 6 was verified using 1 H NMR.
  • compound 7 (TCI, 50 g, Cholesterol chloroformate) was purified by column chromatography (0% to 20% ethyl acetate in n-hexane) filled with 250 g of silica gel to obtain pure compound 7 (30 g). And after adding compound 6 (15 g) and dichloromethane (198.9 g) to a reactor at 10 to 20 ° C., pure compound 7 (30 g) and tetraethylamine (9.6 g) were added in this order, and at 20 to 25 ° C. Stirred for 16 hours. After adding water to the stirred mixture, dichloromethane was added to extract the reaction product.
  • TCI 50% g, Cholesterol chloroformate
  • the extracted organic solution layer was washed with brine, and then moisture was removed using anhydrous sodium sulfate (195 g).
  • the organic solution layer from which moisture was removed was filtered using a filter and then concentrated under low pressure.
  • the concentrated reaction product was prepared using a mixed solution of methyl tert-butyl ether and methanol (10/1, v/v). After separation using a filter, the mixture was dried under low pressure to obtain compound 8 (10.2 g, 55.1%, white solid).
  • the structure of the obtained compound 8 was verified using 1 H NMR. Through 1 H NMR results, it was confirmed that a conjugate in which resiquimod (R848) and cholesterol were linked by a carbamate bond was prepared.
  • compound 9 (20 g, 39.6%, yellow gel) was obtained by column chromatography (silica gel, 300 g, 10%-30% ethyl acetate in n-hexane). The structure of the obtained compound 9 was verified using 1 H NMR.
  • Compound 10 was synthesized using the method of Scheme 8 below. More specifically, after adding compound 9 (20 g) and dichloromethane (200 ml) to a reactor at 10 to 15 ° C., bis (2,5-dioxopyrrolidin-1-yl) carbonate (18 g) and tetraethylamine (10.7 g) were added sequentially. After the mixture was stirred at room temperature for 3 hours, distilled water (300 ml) was added, and then dichloromethane (150 ml) was added three times to extract the reaction product. The extracted organic solution layer was washed with brine, and then moisture was removed using anhydrous sodium sulfate (20 g).
  • Example 9 2-((2-((10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13) ,14,15,16,17-tetradecahydro-1H-cyclo[a]phenanthren-3-yloxy)carbonyloxy)ethyl)disulfanyl)ethyl 2-(ethoxymethyl)-1-(2- Synthesis of hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-yl carbamate
  • compound 11 (10.8 g, 37.4%, white solid) was obtained by column chromatography (silica gel, 100 g, 10% to 50% ethyl acetate in n-hexane). The structure of the obtained compound 11 was verified using 1 H NMR. Through 1 H NMR results, it was confirmed that a conjugate in which R848 and cholesterol were cross-linked with disulfide was prepared.
  • Example 10 Synthesis of a conjugate of an antibody with a Toll-like receptor 7 or 8 agonist
  • toll-like receptor 7 or 8 agonists imidazoquinoloine-based agonist, 8-hydroxyadenine-based agonist
  • antibody antibody
  • Pteridone-based agonist 2-aminopyrimidine-based agonist
  • benzoazepine-based agonist thioxoguanosine-based agonist (7) -thia-8-oxoguanosine-based agonist, etc.
  • NH 2 amine group
  • Toll-like receptor 7 or 8 agonists and antibodies can be linked by linkers that are broken by stimuli from various external or internal environments. A representative linker is shown in FIG. 1 .
  • a conjugate of an antibody and a Toll-like receptor 7 or 8 agonist a conjugate in which the function of the Toll-like receptor 7 or 8 agonist is temporarily inhibited and then cleaved and activated under specific conditions is substantially prepared
  • the toll-like receptor 7 or 8 agonist, resiquimod one of the agonists, resiquimod was used to prepare a conjugate linked to the antibody by various bonds.
  • resiquimod (10 mg) and Mal-Val-Cit-PAB-PNP (47.2 mg) were added to 2 ml of dimethylformamide (N,N-Dimethylformamide; DMF) and then dissolved. Then, N,N-diisopropylethylamine (N,N-Diisopropylethylamine; DIPEA) (6.7 ⁇ l) and hydroxybenzotriazole (1-Hydroxybenzotriazole hydrate; 1-HOBt) (315 ⁇ g) were added. Then, the mixture was prepared by stirring at room temperature for 16 hours. The prepared mixture was purified using thin-layer chromatography, and the function of the activation site of the toll-like receptor 7 or 8 agonist was dynamically restored by cathepsin-ratio as a white powder of Resiqui. mode was obtained.
  • an anti-VEGFR2 antibody and tris (chloroethyl) phosphate Tris (2-carboxyethyl) phosphine; TCEP
  • Tris (2-carboxyethyl) phosphine Tris (2-carboxyethyl) phosphine; TCEP
  • TCEP tris (2-carboxyethyl) phosphine
  • the resiquimod conjugate in which the function of the activation site of the toll-like receptor 7 or 8 agonist is kinetically restored by cathepsin-ratio is adjusted to pH 7.4 using 1M Tris buffer, and then mixed with the antibody, A conjugate was prepared by reacting at 22° C. for 30 minutes, and unreacted materials were removed by gel phoresis using a PD-10 column.
  • a reaction was induced between resiquimod, one of the toll-like receptor 7 or 8 agonists in an inactivated state, to which a beta-glucuronidine conjugate was bound, and the sulfurhydryl group of the partially reduced antibody.
  • the antibody and beta-glucuronidine conjugated resiquimod were mixed, and the conjugate was prepared by reacting at 22° C. for 30 minutes, Materials that did not react were removed by gel phoresis using a PD-10 column.
  • the mixture was prepared by stirring at 4° C. for 16 hours. After adding distilled water to the mixture to separate water and dichloromethane layers, sodium sulfate was added to the separated dichloromethane layer and reacted for 16 hours to remove remaining water. And the remaining solution was purified using a silica gel column, and white powdery antibody-bound resiquimod was obtained.
  • Example 11 Synthesis of a conjugate of a Toll-like receptor 7 or 8 agonist and an anticancer agent
  • toll-like receptor 7 or 8 agonists combined with anticancer drugs (imidazoquinoline agonists, hydroxyadenine agonists, pteridone agonists, aminopyrimidine agonists, benzoazepine agonists, thioxoguanosine-based agonists) are active sites of toll-like receptor 7 or 8 agonists, amine group (NH 2 ) sites, carbamates, disulfides, hydrazines, esters, peptides, azides, beta-glucos It can be prepared by reacting with various anticancer agents capable of synthesizing a bond such as ronidine.
  • Toll-like receptor 7 or 8 agonists and anticancer agents can be linked by linkers that are broken by stimuli from various external or internal environments.
  • a conjugate of an anticancer agent and a Toll-like receptor 7 or 8 agonist the function of the Toll-like receptor 7 or 8 agonist is temporarily inhibited, and then a conjugate that is cleaved and activated under specific conditions is substantially produced.
  • one of resiquimod a conjugate linked to an anticancer agent by various bonds was prepared.
  • a conjugate in which a chemo-drug containing amine group and a toll-like receptor 7 or 8 agonist are linked by a disulfide bond so as to be cleaved by a reducing agent First, doxorubicin and tris (chloroethyl) phosphate (Tris (2-carboxyethyl) phosphine; TCEP), one of the anti-cancer agents containing an amine group, were added to a 1 mM EDTA solution (pH 7.4) to reduce the anti-cancer agent containing an amine group. and reacted at 37°C for 1 hour.
  • Tris (2-carboxyethyl) phosphine Tris (2-carboxyethyl) phosphine
  • dehydroascorbic acid was added to adjust the pH to 6.5, and the mixture was reacted for 1 hour to oxidize again. Afterwards, it induces a reaction between disulfide in a reduced state that is not oxidized and a linker including resiquimod. More specifically, after adjusting the pH to 7.4 using 1M Tris buffer, the oxidized anticancer agent and resiquimod were mixed, and reacted at 22° C. for 30 minutes to prepare a conjugate, and the unreacted substances were collected on the PD-10 column.
  • a typical type of anticancer agent containing an amine group an example of a conjugate of an anticancer agent containing an amine group having a bond cleaved by a reducing agent and a Toll-like receptor 7 or 8 agonist, and the mechanism of cleavage by a reducing agent are shown in FIG. indicated.
  • a conjugate in which an anticancer agent and a Toll-like receptor 7 or 8 agonist are linked by a hydrazine bond was synthesized so that it could be cleaved under acidic conditions in the cell. More specifically, in dichloromethane (3ml), one of toll-like receptor 7 or 8 agonists resiquimod (31.4 mg) and pyridine (100 ⁇ l) were added and dissolved in a solution containing aryl hydrazine (90 mg) and an amine group A solution of doxorubicin (31.4 mg), which is one of the anticancer drugs being used, was slowly added dropwise to a solution of dichloromethane (1ml). Then, the mixture was prepared by stirring at 4° C. for 16 hours.
  • beta-glucuronidase To be cleaved by beta-glucuronidase ( ⁇ -Glucuronidase), a conjugate in which an anticancer agent and a toll-like receptor 7 or 8 agonist are linked by a beta-glucuronide bond was synthesized. More specifically, nitrophenyl beta-gluconide (4-gluconide (4- Nitrophenyl ⁇ -D-glucuronide) (90 mg) and a dichloromethane (1 ml) solution containing paclitaxel (31.4 mg), one of the anticancer drugs containing a hydroxyl group, were slowly added drop by drop. Then, the mixture was prepared by stirring at 4° C. for 16 hours.
  • Example 12 Synthesis of a conjugate of a toll-like receptor 7 or 8 agonist and a protein-based drug
  • toll-like receptor 7 or 8 agonists imidazoquinoline agonists, hydroxyadenine agonists, pteridone agonists, aminopyrimidines Agonists, benzoazepine-based agonists, thioxoguanosine-based agonists, etc.
  • amine group (NH 2 ) site which is the activation site for toll-like receptor 7 or 8 agonists, and carbamates, disulfides, hydrazines, and esters.
  • peptide, azide, beta- various protein-based drugs capable of synthesizing bonds such as glucuronidine can be prepared by reaction.
  • Toll-like receptor 7 or 8 agonists and protein-based drugs can be linked by linkers that are broken by stimuli from a variety of external or internal environments.
  • a conjugate of a protein-based drug and a Toll-like receptor 7 or 8 agonist the function of the Toll-like receptor 7 or 8 agonist is temporarily inhibited, and the conjugate that is activated by cleavage under certain conditions is substantially
  • resiquimod one of the agonists, was used to prepare a conjugate linked to a protein-based drug and various bonds.
  • a representative linker and linkage mechanism for the manufacture of the conjugate are shown in FIG. 6 .
  • the NHS ester reaction was used. More specifically, after adjusting the pH to 6.5 by adding dehydroascorbic acid to the NHS ester (3-Mercaptopropyl-N-hydroxysuccinimide ester) at 22 ° C., the reaction was conducted for 1 hour to prepare a linkage. .
  • the NHS ester reaction was used to synthesize a conjugate in which a protein-based drug and a toll-like receptor 7 or 8 agonist are linked by a hydrazine bond so that they can be cleaved under the concentration of hydrogen ions inside the cell, that is, under acidic conditions. More specifically, dichloromethane (1ml) containing aryl hydrazine (90mg) was slowly added dropwise to dichloromethane (3ml) containing NHS ester (3-Mercaptopropyl-N-hydroxysuccinimide ester) and pyridine (100 ⁇ l). gave.
  • protein antigen OVA (11.4 mg) and resiquimod (31.4 mg), which are one of the protein-based drugs, were added to the mixture, and the mixture was stirred at 4° C. for 16 hours to synthesize a conjugate.
  • the synthesized conjugate was purified using a silica gel column, and white powdery protein-based drug bound resiquimod was obtained.
  • An example of a conjugate of a protein-based drug having a bond cleaved by the concentration of hydrogen ions inside the cell and a Toll-like receptor 7 or 8 agonist, and the cleavage mechanism are shown in FIG. 8 .
  • the NHS ester reaction was used. More specifically, in dichloromethane (3ml) containing resiquimod (31.4mg), NHS ester (3-Mercaptopropyl-N-hydroxysuccinimide ester) and pyridine (100 ⁇ l), nitrophenyl beta-gluconide (4-Nitrophenyl ⁇ - D-glucuronide) (90 mg) added dichloromethane (1 ml) was slowly added dropwise.
  • a maleimide reaction was used.
  • a maleimide reaction was reacted for 1 hour to prepare a linkage.
  • a reaction was induced between the linker containing disulfide in the reduced state that was not oxidized and the protein antigen OVA (31.4 mg), one of the protein-based drugs.
  • a protein-based drug bound to a linker and resiquimod (31.4 mg) were mixed, and reacted at 22° C. for 30 minutes. And the unreacted materials were removed by gel phoresis using a PD-10 column.
  • An example of a conjugate of a protein-based drug having a bond cleaved by a reducing agent and a toll-like receptor 7 or 8 agonist through a sulfhydryl group reaction, and the cleavage mechanism are shown in FIG. 10 .
  • maleimide reaction was used to synthesize the protein-based drug so that it can be cleaved at the concentration of hydrogen ions inside the cell, that is, under acidic conditions. More specifically, dichloromethane (1 ml) containing aryl hydrazine (90 mg) was slowly added dropwise to dichloromethane (3 ml) containing maleimide polyethylene glycol (maleimide PEG) and pyridine (100 ⁇ l).
  • protein antigen OVA (11.4 mg) and resiquimod (31.4 mg), which are one of the protein-based drugs, were added to the mixture, and the mixture was stirred at 4° C. for 16 hours to synthesize a conjugate.
  • the synthesized conjugate was purified using a silica gel column, and white powdery protein-based drug bound resiquimod was obtained.
  • An example of a conjugate of a protein-based drug having a bond cleaved by the concentration of hydrogen ions inside the cell and a Toll-like receptor 7 or 8 agonist, and the cleavage mechanism are shown in FIG. 11 .
  • a maleimide reaction was used to synthesize a protein-based drug and a conjugate in which a toll-like receptor 7 or 8 agonist is linked to beta-glucuronide so that it can be cleaved by beta-glucuronidase. More specifically, nitrophenyl beta-glucuronide (4-Nitrophenyl ⁇ -D-glucuronide) (90mg) in dichloromethane (3ml) added with maleimide polyethylene glycol (maleimide PEG) and pyridine (100 ⁇ l) dichloromethane (1ml) was slowly added dropwise. Then, after adjusting the pH to 9.0, the mixture was prepared by stirring at 4° C. for 16 hours.
  • An example of a conjugate of a protein-based drug having a bond cleaved by beta-glucuronidase and a toll-like receptor 7 or 8 agonist, and the cleavage mechanism are shown in FIG. 12 .
  • Example 13 Synthesis of a conjugate of a Toll-like receptor 7 or 8 agonist with a sensitizer
  • a reaction was induced between photofrin and resiquimod in a reduced state that was not oxidized. More specifically, after adjusting the pH to 7.4 using 1M Tris buffer, the oxidized sensitizer and resiquimod were mixed, and reacted at 22° C. for 30 minutes to prepare a conjugate, and the unreacted materials were PD-10. It was removed by gel phoresis using a column. Representative types of sensitizers, examples of conjugates of a sensitizer having a bond cleaved by a reducing agent and a Toll-like receptor 7 or 8 agonist, and a cleavage mechanism are shown in FIG. 13 .
  • a conjugate in which a sensitizer and a Toll-like receptor 7 or 8 agonist are linked by a hydrazine bond was synthesized so that it could be cleaved at the concentration of hydrogen ions inside the cell, that is, under acidic conditions. More specifically, in dichloromethane (3ml), one of the toll-like receptor 7 or 8 agonists, resiquimod (31.4 mg) and pyridine (100 ⁇ l) were added and dissolved in a solution in which aryl hydrazine (90 mg) was added. A solution of dichloromethane (1 ml) was slowly added dropwise. Then, the mixture was prepared by stirring at 4° C. for 16 hours.
  • Photofrin one of the photosensitizers, was added to the mixture, and reacted at 22° C. for 30 minutes to prepare a conjugate, distilled water was added to separate the water and dichloromethane layers, and then sodium sulfate was added to the separated dichloromethane layer. and reacted for 16 hours to remove the remaining water. And the remaining solution was purified using a silica gel column, and white powder of anticancer agent bound resiquimod was obtained.
  • An example of a conjugate of a sensitizer containing a carboxyl group having a bond cleaved under acidic conditions and a toll-like receptor 7 or 8 agonist, and the cleavage mechanism are shown in FIG. 14 .
  • a conjugate in which a sensitizer and a toll-like receptor 7 or 8 agonist are linked by a beta-glucuronide bond was synthesized. More specifically, in dichloromethane (3ml), one of the toll-like receptor 7 or 8 agonists resiquimod (31.4 mg) and pyridine (100 ⁇ l) were added and dissolved in a solution of nitrophenyl beta-gluconide (90 mg) The added dichloromethane (1ml) solution was slowly added dropwise. Then, the mixture was prepared by stirring at 4° C. for 16 hours.
  • Photofrin one of the photosensitizers, was added to the mixture, and reacted at 22° C. for 30 minutes to prepare a conjugate, distilled water was added to separate the water and dichloromethane layers, and then sodium sulfate was added to the separated dichloromethane layer. and reacted for 16 hours to remove the remaining water. And the remaining solution was purified using a silica gel column, and white powder of anticancer agent bound resiquimod was obtained.
  • An example of a conjugate of a sensitizer containing a carboxyl group having a bond cleaved by beta-glucuronidase and a Toll-like receptor 7 or 8 agonist, and the cleavage mechanism are shown in FIG. 15 .
  • Example 14 Conjugate of an antibody containing a carboxyl group having a bond cleaved by hydrolysis and resiquimod
  • toll-like receptor 7 or 8 agonists were synthesized. More specifically, resiquimod (10 mg) and maleimide-polyethyl glycol-hydroxysuccinimide (Maleimide-dPEG 4 -NHS ester) (19.6 mg) were added to dichloromethane (DCM) (2 ml). Afterwards, triethylamine (8.8 ⁇ L) was added.
  • DCM dichloromethane
  • the mixture was prepared by stirring at room temperature for 16 hours, and the mixture was purified using thin-layer chromatography, and the function of the activated site was dynamically restored by hydrolysis of white powder.
  • Quimod was obtained.
  • the anti-VEGFR2 antibody (4mg) was dispersed in 1M borate buffer containing 1mM diethylenetriamine (DTPA).
  • DTPA diethylenetriamine
  • TCEP tris(2-carboxyethyl)phosphine
  • the reduced antibody and resiquimod 210 ⁇ g
  • the antibody-resiquimod conjugate (AAC-001) was purified by centrifugation at 1,000 ⁇ g for 2 minutes using a zeba TM desalting column.
  • the anticancer effect was evaluated using B16OVA melanoma.
  • 5 ⁇ 10 5 cells of B16OVA cancer cells were subcutaneously injected into the back of the rat, and the drug was directly injected into the cancer tissue 4 times at intervals of 3 days from 3 days later.
  • drugs resiquimod, a mixture of resiquimod and anti-VEGFR2, an anti-VEGFR2 antibody having a bond cleaved by hydrolysis, and a conjugate of resiquimod (AAC-001) were used.
  • the AAC-001 conjugate inhibited the growth of cancer compared to resiquimod alone (R848) as well as anti-VEGFR2 and resiquimod combined administration (R848+anti-VEGFR2). It was confirmed that not only markedly suppressed, but also increased the survival rate.
  • Example 14.1 In order to confirm the effect of the antibody-resiquimod conjugate (AAC-001) synthesized in the same manner as in Example 14.1 on the secretion of inflammatory cytokines in the blood, intravenous injection of the AAC-001 conjugate or resiquimod into mice, respectively After that, blood was collected at 0, 1, 2, and 4 hours. The collected blood samples were centrifuged at 10,000 ⁇ g for 20 minutes to separate serum, and the concentration of IL-6, a representative inflammatory cytokine, present in the serum was measured using the Invitrogen mouse IL-6 ELISA kit. The results are shown in FIG. 18 .
  • a cytokine storm is induced by promoting the secretion of inflammatory cytokines as soon as they are injected into the body, but it was confirmed that the amount of inflammatory cytokines did not change in the case of AAC-001 conjugate. did.
  • the conjugate of the antibody of the present invention and a Toll-like receptor 7 or 8 agonist that is, a conjugate in which the antibody is bonded to the activation site of the Toll-like receptor 7 or 8 agonist with a cleavable linker, is initially administered.
  • a functional drug such as an antibody acts, and the Toll-like receptor 7 or 8 agonist is temporarily inactive, and the linker is cleaved by a hydrolytic enzyme in the tumor microenvironment or target cell to cut the Toll-like receptor 7 or 8. It could be confirmed that, as the agonist was activated, the immune activation effect was secondary, resulting in lower side effects and significantly increased therapeutic effect compared to simple combined administration.
  • Example 15 A conjugate of an antibody containing a carboxyl group having a bond cleaved by cathepsin-ratio and resiquimod
  • resiquimod in which a linker is bound to the activation site was synthesized. More specifically, resiquimod (10 mg) and Mal-Val-Cit-PAB-PNP (47.2 mg) were added to 2 ml of dimethylformamide (N,N-Dimethylformamide; DMF) and then dissolved.
  • N,N-diisopropylethylamine N,N-Diisopropylethylamine; DIPEA
  • hydroxybenzotriazole (1-Hydroxybenzotriazole hydrate; 1-HOBt) (315 ⁇ g) were added.
  • the mixture was prepared by stirring at room temperature for 16 hours.
  • the prepared mixture was purified using thin-layer chromatography, and the function of the activation site of the toll-like receptor 7 or 8 agonist was dynamically restored by cathepsin-ratio as a white powder of Resiqui. mode was obtained.
  • a conjugate (AAC-002) of an antibody having a bond cleaved by cathepsin-ratio and resiquimod was synthesized.
  • the anti-SIRP ⁇ antibody (4mg) was dispersed in 1M borate buffer containing 1mM diethylenetriamine (DTPA), and then 150 ⁇ M of tris(2-carboxyethyl)phosphine (TCEP) was added and The antibody was reduced by stirring at 37° C. for 1 hour.
  • the partially reduced antibody and resiquimod (480 ⁇ g) in which the function of the activation site is dynamically restored were mixed and stirred at 4° C. for 1 hour to synthesize a conjugate.
  • AAC-002 is a conjugate of the antibody and resiquimod.
  • the mechanism of the AAC-002 conjugate is shown in FIG. 19 .
  • the AAC-002 conjugate (Conjugated TLR7/8a-Blocked active site) was intravenously injected into rats, and blood was collected 2 hours later. The collected blood samples were centrifuged at 10,000 ⁇ g for 20 minutes to separate serum, and the concentration of IL-6, a representative inflammatory cytokine, present in the serum was measured using the Invitrogen mouse IL-6 ELISA kit.
  • Example 16 Conjugate of a protein antigen having a bond cleaved by cathepsin-ratio and resiquimod
  • resiquimod which is one of the protein-based drugs containing a sulfhydryl group having a bond cleaved by cathepsin-ratio
  • resiquimod in which a linker is bound to the activation site was synthesized.
  • resiquimod (10 mg) and Mal-Val-Cit-PAB-PNP (47.2 mg) were added to 2 ml of dimethylformamide (N,N-Dimethylformamide; DMF), and then dissolved.
  • N,N-diisopropylethylamine N,N-Diisopropylethylamine; DIPEA
  • hydroxybenzotriazole (1-Hydroxybenzotriazole hydrate; 1-HOBt) (315 ⁇ g) were added.
  • the mixture was prepared by stirring at room temperature for 16 hours.
  • OVA protein antigen (10 mg) was added to the prepared mixture and reacted to prepare a conjugate, and then purified using thin-layer chromatography, and OVA protein having a bond cleaved by cathepsin-ratio A conjugate of antigen and resiquimod was prepared. And the size of the prepared binder was confirmed using spectroscopic analysis. The results are shown in FIG. 21 .
  • a functional drug is bound to the active site of the toll-like receptor 7 or 8 agonist and the activity is temporarily inhibited, When injected into inflammatory cytokine secretion and non-specific immune response is suppressed, it does not show toxicity, so side effects can be significantly reduced. 8
  • the agonist and the functional drug are separated, and the delivery power can be increased.
  • the therapeutic effect can be significantly increased. confirmed that it is possible. Therefore, it is expected that the conjugate of the present invention in which the activation site of a toll-like receptor 7 or 8 agonist and a functional drug are linked by a cleavable linker can be effectively used in the treatment of various diseases.
  • the conjugate in which the activation site of the Toll-like receptor 7 or 8 agonist of the present invention and the functional drug are linked by a cleavable linker is temporarily inactive when administered into the body. Since the receptor-like receptor 7 or 8 agonist and the functional drug are separated and activated, side effects such as non-specific hypersensitivity immune response can be lowered, and at the same time, the functional drug can be effectively regulated by the Toll-like receptor 7 or 8 agonist. Because of this action, the therapeutic effect can be significantly improved. Therefore, it is applicable to all functional drugs that can be administered in combination with a Toll-like receptor 7 or 8 agonist.

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